The long-term objectives of this research proposal are to define the signaling pathways that regulate hematopoietic progenitor cell survival. Our lab has demonstrated that Bcl-XL is selectively regulated by survival factors, and that this Bcl-2 family member is selectively activated in T-cell and Myeloid malignancies. Preliminary investigations have demonstrated that Jak kinase signaling pathways are both necessary and sufficient for regulation of Bcl-XL, whereas other signaling pathways implicated as regulators of apoptosis, such as Ras, STAT, and PI-3'/Akt kinase pathways, fail to regulate Bcl-XL and are dispensable for cell survival. Additionally, bcl-x and Jak-2 knockouts show marked defects in hematopoiesis pointing towards Bcl-XL and Jak-2 kinase playing critical roles in the programmed cell deaths of hematopoietic progenitors. Both genetic (knockout and knock-in mice) and biochemical (protein levels, promoter regulatory sites, subcellular localization, and post-translational modifications) approaches will be used to determine how the protein levels of Bcl-2 family members are regulated, as well as what regulates their gene expression. These studies will help further our understanding of the regulation of apoptosis in hematopoiesis.